tbuckley/cabot-search huggingface dataset:
SARS-CoV-2 molecular epidemiology in Slovenia, January to September 2021
Authors: Sandra Janezic, Aleksander Mahnic, Urška Kuhar, Jernej Kovač, Barbara Jenko Bizjan, Tom Koritnik, Tine Tesovnik, Robert Šket, Uroš Krapež, Brigita Slavec, Tadej Malovrh, Tadej Battelino, Maja Rupnik, Tjasa Zohar Cretnik
Journal: Eurosurveillance (2023)

BackgroundSequencing of SARS-CoV-2 PCR-positive samples was introduced in Slovenia in January 2021. Our surveillance programme comprised three complementary schemes: (A) non-targeted sequencing of at least 10% of samples, (B) sequencing of samples positive after PCR screening for variants of concern (VOC) and (C) sequencing as per epidemiological indication.AimWe present the analysis of cumulative data of the non-targeted surveillance of SARS-CoV-2 and variant-dependent growth kinetics for the five most common variants in Slovenia for the first 9 months of 2021.MethodsSARS-CoV-2 PCR-positive samples, from January to September 2021, were selected for sequencing according to the national surveillance plan. Growth kinetics studies were done on Vero E6 cells.ResultsAltogether 15,175 genomes were sequenced and 64 variants were detected, of which three successively prevailed. Variant B.1.258.17 was detected in ca 80% of samples in January and was replaced, within 9 weeks, by the Alpha variant. The number of cases decreased substantially during the summer of 2021. However, the introduction of the Delta variant caused a fourth wave and completely outcompeted other variants. Other VOC were only detected in small numbers. Infection of Vero E6 cells showed higher replication rates for the variants Alpha and Delta, compared with B.1.258.17, B.1.258, and B.1.1.70, which dominated in Slovenia before the introduction of the Alpha and Delta variants.ConclusionInformation on SARS-CoV-2 variant diversity provided context to the epidemiological data of PCR-positive cases, contributed to control of the initial spread of known VOC and influenced epidemiological measures.
Genome-wide CRISPR/Cas9 screens reveal shared and cell-specific mechanisms of resistance to SHP2 inhibition
Authors: Wei Wei, Mitchell J. Geer, Xinyi Guo, Igor Dolgalev, Neville E. Sanjana, Benjamin G. Neel
Journal: The Journal of Experimental Medicine (2023)

SHP2 (PTPN11) acts upstream of SOS1/2 to enable RAS activation. Allosteric SHP2 inhibitors (SHP2i) in the clinic prevent SHP2 activation, block proliferation of RTK- or cycling RAS mutant-driven cancers, and overcome “adaptive resistance.” To identify SHP2i resistance mechanisms, we performed genome-wide CRISPR/Cas9 knockout screens on two SHP2i-sensitive cell lines, recovering genes expected to cause resistance (NF1, PTEN, CDKN1B, LZTR1, and RASA2) and novel targets (INPPL1, MAP4K5, epigenetic modifiers). We screened 14 additional lines with a focused CRISPR library targeting common “hits” from the genome-wide screens. LZTR1 deletion conferred resistance in 12/14 lines, followed by MAP4K5 (8/14), SPRED2/STK40 (6/14), and INPPL1 (5/14). INPPL1, MAP4K5, or LZTR1 deletion reactivated ERK signaling. INPPL1-mediated sensitization to SHP2i required its NPXY motif but not lipid phosphatase activity. MAP4K5 acted upstream of MEK through a kinase-dependent target(s); LZTR1 had cell-dependent effects on RIT and RAS stability. INPPL1, MAP4K5, or LZTR1 deletion also conferred SHP2i resistance in vivo. Defining the SHP2i resistance landscape could suggest effective combination approaches.
Epidemiology of Herpes Zoster in the pre-vaccination era: establishing the baseline for vaccination programme’s impact in Spain
Authors: Carlos Risco Risco, Zaida Herrador, Noemí Lopez-Perea, Diego Martínez-Urbistondo, Rafael Suárez del Villar Carrero, Josefa Masa-Calles
Journal: Eurosurveillance (2023)

BackgroundHerpes zoster (HZ) affects 1 in 3 persons in their lifetime, and the risk of HZ increases with increasing age and the presence of immunocompromising conditions. In Spain, vaccination guidelines were recently updated to include the recommendation of the new recombinant zoster vaccine (RZV) for certain risk groups.AimTo describe the epidemiology of HZ-related hospitalisations in Spain in order to prioritise vaccination recommendations and define a baseline to monitor the effectiveness of vaccination policies.MethodsRetrospective study using the National Health System's Hospital Discharge Records Database, including all HZ-related hospitalisations from 1998 to 2018.ResultsThe 65,401 HZ-related hospitalisations, corresponded to an annual mean hospitalisation rate of 6.75 per 100,000 population. There was an increasing trend of HZ hospitalisations over the study period. This rate was higher in males and older age groups, particularly over 65 years. Comorbidities with higher risk of readmission were leukaemia/lymphoma (RR 2.4; 95% CI: 2.3-2.6) and solid malignant neoplasm (RR 2.2; 95% CI: 2.1-2.4). Comorbidities associated with higher risk of mortality were leukaemia/lymphoma (RR 2.9; 95% CI: 2.7-3.2), solid malignant neoplasm (RR 2.9; 95% CI: 2.7-3.1) and HIV infection (RR 2.2; 95% CI: 1.8-2.7).ConclusionOf all patients hospitalised with HZ, those with greater risk of mortality or readmission belonged to the groups prioritised by the current vaccination recommendations of the Spanish Ministry of Health. Our study provided relevant information on clinical aspects of HZ and established the base for future assessments of vaccination policies.
Gut microbial metabolism of 5-ASA diminishes its clinical efficacy in inflammatory bowel disease
Authors: Raaj S. Mehta, Jared R. Mayers, Yancong Zhang, Amrisha Bhosle, Nathaniel R. Glasser, Long H. Nguyen, Wenjie Ma, Sena Bae, Tobyn Branck, Kijun Song, Luke Sebastian, Julian Avila Pacheco, Hyuk-Soo Seo, Clary Clish, Sirano Dhe-Paganon, Ashwin N. Ananthakrishnan, Eric A. Franzosa, Emily P. Balskus, Andrew T. Chan, Curtis Huttenhower
Journal: Nature Medicine (2023)
Brain expression quantitative trait locus and network analyses reveal downstream effects and putative drivers for brain-related diseases
Authors: Niek de Klein, Ellen A. Tsai, Martijn Vochteloo, Denis Baird, Yunfeng Huang, Chia-Yen Chen, Sipko van Dam, Roy Oelen, Patrick Deelen, Olivier B. Bakker, Omar El Garwany, Zhengyu Ouyang, Eric E. Marshall, Maria I. Zavodszky, Wouter van Rheenen, Mark K. Bakker, Jan Veldink, Tom R. Gaunt, Heiko Runz, Lude Franke, Harm-Jan Westra
Journal: Nature Genetics (2023)

Identification of therapeutic targets from genome-wide association studies (GWAS) requires insights into downstream functional consequences. We harmonized 8,613 RNA-sequencing samples from 14 brain datasets to create the MetaBrain resource and performed cis- and trans-expression quantitative trait locus (eQTL) meta-analyses in multiple brain region- and ancestry-specific datasets (n ≤ 2,759). Many of the 16,169 cortex cis-eQTLs were tissue-dependent when compared with blood cis-eQTLs. We inferred brain cell types for 3,549 cis-eQTLs by interaction analysis. We prioritized 186 cis-eQTLs for 31 brain-related traits using Mendelian randomization and co-localization including 40 cis-eQTLs with an inferred cell type, such as a neuron-specific cis-eQTL (CYP24A1) for multiple sclerosis. We further describe 737 trans-eQTLs for 526 unique variants and 108 unique genes. We used brain-specific gene-co-regulation networks to link GWAS loci and prioritize additional genes for five central nervous system diseases. This study represents a valuable resource for post-GWAS research on central nervous system diseases.
Characterizing Moral Injury and Distress in US Military Surgeons Deployed to Far-Forward Combat Environments in Afghanistan and Iraq
Authors: Madeline Y. Ryu, Matthew J. Martin, Alexander H. Jin, Holly K. Tabor, Sherry M. Wren
Journal: JAMA Network Open (2023)

Importance Moral injury and distress (MID), which occurs when individuals have significant dissonance with their belief system and overwhelming feelings of being powerless to do what is believed to be right, has not been explored in the unique population of military surgeons deployed far forward in active combat settings. Deployed military surgeons provide care to both injured soldiers and civilians under command-driven medical rules of engagement (MROE) in variably resourced settings. This practice setting has no civilian corollary for comparison or current specific tool for measurement. Objective To characterize MID among military surgeons deployed during periods of high casualty volumes through a mixed-methods approach. Design, Setting, and Participants This qualitative study using convergent mixed methods was performed from May 2020 to October 2020. Participants included US military surgeons who had combat deployments to a far-forward role 2 treatment facility during predefined peak casualty periods in Iraq (2003-2008) and Afghanistan (2009-2012), as identified by purposeful snowball sampling. Data analysis was performed from October 2020 to May 2021. Main Outcomes and Measures Measure of Moral Distress for Healthcare Professionals (MMD-HP) survey and individual, semistructured interviews were conducted to thematic saturation. Results The total cohort included 20 surgeons (mean [SD] age, 38.1 [5.2] years); 16 (80%) were male, and 16 (80%) had 0 or 1 prior deployment. Deployment locations were Afghanistan (11 surgeons [55%]), Iraq (9 surgeons [45%]), or both locations (3 surgeons [15%]). The mean (SD) MMD-HP score for the surgeons was 104.1 (39.3). The primary thematic domains for MID were distressing outcomes (DO) and MROE. The major subdomains of DO were guilt related to witnessing horrific injuries; treating pregnant women, children, and US soldiers; and second-guessing decisions. The major subdomains for MROE were forced transfer of civilian patients, limited capabilities and resources, inexperience in specialty surgical procedures, and communication with command. Postdeployment manifestations of MID were common and affected sleep, medical practice, and interpersonal relationships. Conclusions and Relevance In this qualitative study, MID was ubiquitous in deployed military surgeons. Thematic observations about MID, specifically concerning the domains of DO and MROE, may represent targets for further study to develop an evaluation tool of MID in this population and inform possible programs for identification and mitigation of MID.
The impact of inconsistent human annotations on AI driven clinical decision making
Authors: Aneeta Sylolypavan, Derek Sleeman, Honghan Wu, Malcolm Sim
Journal: npj Digital Medicine (2023)

In supervised learning model development, domain experts are often used to provide the class labels (annotations). Annotation inconsistencies commonly occur when even highly experienced clinical experts annotate the same phenomenon (e.g., medical image, diagnostics, or prognostic status), due to inherent expert bias, judgments, and slips, among other factors. While their existence is relatively well-known, the implications of such inconsistencies are largely understudied in real-world settings, when supervised learning is applied on such 'noisy' labelled data. To shed light on these issues, we conducted extensive experiments and analyses on three real-world Intensive Care Unit (ICU) datasets. Specifically, individual models were built from a common dataset, annotated independently by 11 Glasgow Queen Elizabeth University Hospital ICU consultants, and model performance estimates were compared through internal validation (Fleiss' κ = 0.383 i.e., fair agreement). Further, broad external validation (on both static and time series datasets) of these 11 classifiers was carried out on a HiRID external dataset, where the models' classifications were found to have low pairwise agreements (average Cohen's κ = 0.255 i.e., minimal agreement). Moreover, they tend to disagree more on making discharge decisions (Fleiss' κ = 0.174) than predicting mortality (Fleiss' κ = 0.267). Given these inconsistencies, further analyses were conducted to evaluate the current best practices in obtaining gold-standard models and determining consensus. The results suggest that: (a) there may not always be a "super expert" in acute clinical settings (using internal and external validation model performances as a proxy); and (b) standard consensus seeking (such as majority vote) consistently leads to suboptimal models. Further analysis, however, suggests that assessing annotation learnability and using only 'learnable' annotated datasets for determining consensus achieves optimal models in most cases.
Nutrient regulation of the islet epigenome controls adaptive insulin secretion
Authors: Matthew Wortham, Fenfen Liu, Austin R. Harrington, Johanna Y. Fleischman, Martina Wallace, Francesca Mulas, Medhavi Mallick, Nicholas K. Vinckier, Benjamin R. Cross, Joshua Chiou, Nisha A. Patel, Yinghui Sui, Carolyn McGrail, Yesl Jun, Gaowei Wang, Ulupi S. Jhala, Roland Schüle, Orian S. Shirihai, Mark O. Huising, Kyle J. Gaulton, Christian M. Metallo, Maike Sander
Journal: Journal of Clinical Investigation (2023)

Adaptation of the islet β cell insulin-secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we have shown that nutrient-stimulated histone acetylation plays a key role in adapting insulin secretion through regulation of genes involved in β cell nutrient sensing and metabolism. Nutrient regulation of the epigenome occurred at sites occupied by the chromatin-modifying enzyme lysine-specific demethylase 1 (Lsd1) in islets. β Cell-specific deletion of Lsd1 led to insulin hypersecretion, aberrant expression of nutrient-response genes, and histone hyperacetylation. Islets from mice adapted to chronically increased insulin demand exhibited shared epigenetic and transcriptional changes. Moreover, we found that genetic variants associated with type 2 diabetes were enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined and clinically relevant. Overall, these studies revealed that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome.
Application of Genomic Sequencing to Refine Patient Stratification for Adjuvant Therapy in Renal Cell Carcinoma
Authors: Naveen S. Vasudev, Ghislaine Scelo, Kate I. Glennon, Michelle Wilson, Louis Letourneau, Robert Eveleigh, Nazanin Nourbehesht, Madeleine Arseneault, Antoine Paccard, Lars Egevad, Juris Viksna, Edgars Celms, Sharon M. Jackson, Behnoush Abedi-Ardekani, Anne Y. Warren, Peter J. Selby, Sebastian Trainor, Michael Kimuli, Jon Cartledge, Naeem Soomro, Adebanji Adeyoju, Poulam M. Patel, Magdalena B. Wozniak, Ivana Holcatova, Antonin Brisuda, Vladimir Janout, Estelle Chanudet, David Zaridze, Anush Moukeria, Oxana Shangina, Lenka Foretova, Marie Navratilova, Dana Mates, Viorel Jinga, Ljiljana Bogdanovic, Bozidar Kovacevic, Anne Cambon-Thomsen, Guillaume Bourque, Alvis Brazma, Jörg Tost, Paul Brennan, Mark Lathrop, Yasser Riazalhosseini, Rosamonde E. Banks
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Patients with resected localized clear-cell renal cell carcinoma (ccRCC) remain at variable risk of recurrence. Incorporation of biomarkers may refine risk prediction and inform adjuvant treatment decisions. We explored the role of tumor genomics in this setting, leveraging the largest cohort to date of localized ccRCC tissues subjected to targeted gene sequencing. Experimental Design: The somatic mutation status of 12 genes was determined in 943 ccRCC cases from a multinational cohort of patients, and associations to outcomes were examined in a Discovery (n = 469) and Validation (n = 474) framework. Results: Tumors containing a von-Hippel Lindau (VHL) mutation alone were associated with significantly improved outcomes in comparison with tumors containing a VHL plus additional mutations. Within the Discovery cohort, those with VHL+0, VHL+1, VHL+2, and VHL+≥3 tumors had disease-free survival (DFS) rates of 90.8%, 80.1%, 68.2%, and 50.7% respectively, at 5 years. This trend was replicated in the Validation cohort. Notably, these genomically defined groups were independent of tumor mutational burden. Amongst patients eligible for adjuvant therapy, those with a VHL+0 tumor (29%) had a 5-year DFS rate of 79.3% and could, therefore, potentially be spared further treatment. Conversely, patients with VHL+2 and VHL+≥3 tumors (32%) had equivalent DFS rates of 45.6% and 35.3%, respectively, and should be prioritized for adjuvant therapy. Conclusions: Genomic characterization of ccRCC identified biologically distinct groups of patients with divergent relapse rates. These groups account for the ∼80% of cases with VHL mutations and could be used to personalize adjuvant treatment discussions with patients as well as inform future adjuvant trial design.
The development of a rapid patient-derived xenograft model to predict chemotherapeutic drug sensitivity/resistance in malignant glial tumors
Authors: Martine Charbonneau, Kelly Harper, Karine Brochu-Gaudreau, Alexis Perreault, Laurent-Olivier Roy, Fabrice Lucien, Shulan Tian, David Fortin, Claire M Dubois
Journal: Neuro-Oncology (2023)

High-grade gliomas (HGG) are aggressive brain tumors associated with short median patient survival and limited response to therapies, driving the need to develop tools to improve patient outcomes. Patient-derived xenograft (PDX) models, such as mouse PDX, have emerged as potential Avatar platforms for personalized oncology approaches, but the difficulty for some human grafts to grow successfully and the long time required for mice to develop tumors preclude their use for HGG.We used a rapid and efficient ex-ovo chicken embryo chorioallantoic membrane (CAM) culture system to evaluate the efficacy of oncologic drug options for HGG patients.Implantation of fresh glioma tissue fragments from 59 of 60 patients, that include difficult-to-grow IDH-mutated samples, successfully established CAM tumor xenografts within 7 days, with a tumor take rate of 98.3%. These xenografts faithfully recapitulate the histological and molecular characteristics of the primary tumor, and the ability of individual fragments to form tumors was predictive of poor patient prognosis. Treatment of drug-sensitive or drug-resistant xenografts indicates that the CAM-glioma assay enables testing tumor sensitivity to temozolomide and carboplatin at doses consistent with those administered to patients. In a proof-of-concept study involving 14 HGG patients, we observed a correlation of 100% between the CAM xenograft response to temozolomide or carboplatin and the clinical response of patients.The CAM-glioma model is a fast and reliable assay that has the potential to serve as a complementary model to drug discovery and a real-time Avatar platform to predict the best treatment for HGG patients.
Risk Prediction Models for Cardiotoxicity of Chemotherapy Among Patients With Breast Cancer
Authors: Elisé G. Kaboré, Conor Macdonald, Ahmed Kaboré, Romain Didier, Patrick Arveux, Nicolas Meda, Marie-Christine Boutron-Ruault, Charles Guenancia
Journal: JAMA Network Open (2023)

Cardiotoxicity is a serious adverse effect that can occur in women undergoing treatment for breast cancer. Identifying patients who will develop cardiotoxicity remains challenging.To identify, describe, and evaluate all prognostic models developed to predict cardiotoxicity following treatment in women with breast cancer.This systematic review searched the Medline, Embase, and Cochrane databases up to September 22, 2021, to include studies developing or validating a prediction model for cardiotoxicity in women with breast cancer. The Prediction Model Risk of Bias Assessment Tool (PROBAST) was used to assess both the risk of bias and the applicability of the prediction modeling studies. Transparency reporting was assessed with the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) tool.After screening 590 publications, we identified 7 prognostic model studies for this review. Six were model development studies and 1 was an external validation study. Outcomes included occurrence of cardiac dysfunction (echocardiographic parameters), heart failure, and composite clinical outcomes. Model discrimination, measured by the area under receiver operating curves or C statistic, ranged from 0.70 (95% IC, 0.62-0.77) to 0.87 (95% IC, 0.77-0.96). The most common predictors identified in final prediction models included age, baseline left ventricular ejection fraction, hypertension, and diabetes. Four of the developed models were deemed to be at high risk of bias due to analysis concerns, particularly for sample size, handling of missing data, and not presenting appropriate performance statistics. None of the included studies examined the clinical utility of the developed model. All studies met more than 80% of the items in TRIPOD checklist.In this systematic review of the 6 predictive models identified, only 1 had undergone external validation. Most of the studies were assessed as being at high overall risk of bias. Application of the reporting guidelines may help future research and improve the reproducibility and applicability of prediction models for cardiotoxicity following breast cancer treatment.
Association of Conditional Cash Transfers With Maternal Mortality Using the 100 Million Brazilian Cohort
Authors: Flávia Jôse O. Alves, Dandara Ramos, Enny S. Paixão, Ila R. Falcão, Rita de Cássia Ribeiro-Silva, Rosemeire Fiaccone, Davide Rasella, Camila Teixeira, Daiane Borges Machado, Aline Rocha, Marcia F. de Almeida, Emanuelle F. Goes, Laura C. Rodrigues, Maria Yury Ichihara, Estela M. L. Aquino, Maurício L. Barreto
Journal: JAMA Network Open (2023)

Importance Conditional cash transfers (CCTs) have been consistently associated with improvements to the determinants of maternal health, but there have been insufficient investigations regarding their effects on maternal mortality. Objective To evaluate the association between being a Bolsa Família program (BFP) beneficiary and maternal mortality and to examine how this association differs by duration of BFP receipt, maternal race, living in rural or urban areas, the Municipal Human Development Index (MHDI), and municipal primary health care coverage. Design, Setting, and Participants This cross-sectional analysis was nested within the 100 Million Brazilian Cohort. Girls and women aged 10 to 49 years (hereinafter referred to as women) who had at least 1 live birth were included, using data from Brazilian national health databases linked to the 100 Million Brazilian Cohort (January 1, 2004, to December 31, 2015). Propensity score kernel weighting was applied to control for sociodemographic and economic confounders in the association between BFP receipt and maternal mortality, overall and stratified by different subgroups (race, urban or rural area, and MHDI), and duration of BFP receipt. Data were analyzed from July 12, 2019, to December 31, 2022. Main Outcome(s) and Measures Maternal death. Results A total of 6 677 273 women aged 10 to 49 years were included in the analysis, 4056 of whom had died from pregnancy-related causes. The risk of maternal death was 18% lower in women who received BFP (weighted odds ratio [OR], 0.82 [95% CI, 0.71-0.93]). A longer duration receiving BFP was associated with an increased reduction in maternal mortality (OR for 1-4 years, 0.85 [95% CI, 0.75-0.97]; OR for 5-8 years, 0.70 [95% CI, 0.60-0.82]; OR for ≥9 years, 0.69 [95% CI, 0.53-0.88]). Receiving BFP was also associated with substantial increases in the number of prenatal appointments and interbirth intervals. The reduction was more pronounced in the most vulnerable groups. Conclusions and Relevance This cross-sectional analysis nested within the 100 Million Brazilian Cohort found an association between BFP receipt and maternal mortality. This association was of greater magnitude in women with longer exposure to BFP and in the most vulnerable groups. These findings reinforce evidence that programs such as BFP, which have already proven effective in poverty reduction, have great potential to improve maternal survival.